Anesthetic of the pyridine series and method for producing the same



Potented'lfeb; 6, 12:34()` i, 2,189,404 1 l EL-2,189,464 ,Y l. e e ANE- STHETIC oF THE Piumini: A ,l METHOD FOR PRODU'CINGTHE e Ik noemoremfinenshaw, New York, and from Dreisbah, Yonkers, N. 1Y=.', `v`as/s'gfnos 'to Pyri- .diumeCorporatiom Nepera-lPark, N. -Ywa cor- ;porateioenvof .Newy York l, x

UNITED-- PAT-ENT joFgFlcE-f s' :JN0 Dfawiugy Application February 528, 193.8,j

f e i --Se1'all\lo. 193,079

e l .-efelainsg (CL26oeem` l s Y, e Our invention relates Ato anestheticsvfo'f` the 'I'hese'compounds maybe"representedwith'the pyridine ,series andthe methodof --preparing followingfgen-eralformula:

, Itfhas beenlstated that ltheproductionof -anesy Y e oo'oR-X l :5 thesia is a vproperty of the derivatives r.of 'the 1 'e e Vll Y evenxstated :thatthefbenzoylgrmp'comdotpe in which represents the residue of an unsubreplaced by `vany .other acid1 radlcals-, (Fllehne, Stituted alkyeligrouphaving notmorehan 6 care y lo Bor. klm, Woon. :1887, zp. 107; Erhliohzfanoeuinben-atoms, Re represente the residue of en um 10 l, 110m, Ber- 1394, pv- 1870)'11dthat the benZOYl substituted alkyl group and X frepresents the g1 01110 atedfayafn anestheslphofe groupresidue of an amino compound, alkylamiIlO "00m-f Numerous localanesthetics have been made since pound, dialkylamino Compound or oyclio alkylthe discovery of'v Einhorn, thatmtheTesters'v of pamino .Compound e 1,5 ominobenzoio acidand hydroxybenzoic acid, and R' in the general formula is lan.unsubstlmted '115,

their various. derlvotives'fst I'more Orl-"less 'as saturated alkyl residue, such as ethyltohexylanesthetics., f i

l 'c Y residues, these alkyl radicals being selected from Wehave now found-,uthstvariesthetws*anfbe a group fof'monovalent 'radicals derived :from kla produced from the pyridine'cringe-that' is;A We satratedhydroca'rbon. It'may'befa'normalfor have produced anesthetics bye-esterication of an-,jsomericalkyl group'and it containsfnot more 30 alkyl hydroxypyrdine carboxylic acids- Wefhave than' carbon atoms.v Those with 3 to rcarbon also found that the anesthetics" so lprepared are atoms appear to be the mog-,effective f IESS OXC` than SQme Of the analogous COlfflpfllnds R2 in the general formula represents a satu- @fthe benzenesel'lesrated normal or isomeri alkyl group. yTwo or l .25A V'The ,Object 0f nVentOnwS :tOi-prepare "n -C'a'lrbon atojfns appear fto the de..

anesthetic by .esterication ofp-hydroxypyridine siriable, though higher alkyl groups-'may `loe `used carboxylicacids.y e e l f insome instances, i 1 l Allotherobject of vthis inventioneisfto' prepare illoobtain vthe best Lresults it is "apparent that anesthetics of the pyridine series which Yaremore4 thehydrog'enf'atm's inthe Aamino,groupx Should su effective than .the correspondinecompounds :of be :substituted withy alkyl groups. Thesefalkyl the benzeneseries, AOther objects of thisinv'engroups vagain might ybe diere'ht or alike, 1mi-1t tion can'be seenfrom the specifications. s r is obvious, that :dlalkyl vamines with equal'sub- The. generallfOlmula 0f.,the Simple, esters -0f stitueritsare'easierto obtain. 4

ii-hydroxypyridine carboxylic-'acid may -beorep- 'Imeoompounds prepared according 'to these resented `11111511..- ,r f. ,1- .,z sv specifications fare colorless, basic in bha'ra'cter 35 OsR n 1. i and'formadditionisaltswith minealandorganic acids. -`The lb'ases'of the 'compoundsfin general areinsoluble in Water and soluble in most 'ore i u ganicis'olven-ts. The ysaltsarem'o're 'orflessfsoluble Li0 in which R represents the residueof an alkyl IlvWa'teI- f group. z, v 1., f A We have prepared several of the salts oflthe's'e -Of these simple hydroxypyridine"icarboxylic IlWbaSC COIIIDOUIICS. The hydIOChlOrideS, sulacid` estersonly-the methyly andethyljesters of` fates, heXO'ateS, be'nZOat'eS, Cinnamates and nicotinic acid are known, phenyl acetates, some of which/form diilcultly The hydroxy group may be alkylatod forour crystallizable substances as Will'be noted in this 45 purpose by replacing the hydrogenatonriwith specicationf on alkyl ejroupoontaining up 'to 6 carbonatoms. In general they'h'sve anesthetic properties-and 'Ii'le'carbicy'groupj'may be 'esteriedwith aminov their toxicity is comparatively low. The raw alcohols, 'alkylamino alcohols, 'dia'lkyl-anllino.a1-I material for preparing these-.compoundsare-tm eohols With'two equal or different"alkyl"residuesl chloropyrdine carboxylic acids, made according 50 of any number fof carbon atoms, or with cyclo.- to` 'the' methods `r described in the literature aliphaticresiclues such as the; cyclohexyl group thrughvarious'steps. Forinstance,"6ch1oro3 or cyclohexanyl group. Furthermore, N-alkylcarb'dii'ypyridine (6-cliloro'nictiriic acid) vis pre piperidine residue may be 'falso used for the pared according to the 'nrtli'od of vfPechman, esteriiicationm l f e ,o Welsch, A(Ber. (1884l-2392ly0r otlierfknwn 46.

Example 1 2 gramc=6rnethoxy 4nicotinicfacid (prepared accordi-ngto H."'Meyer,' M. vol.s"28 (19(3'7) p. 59) are dissolved in Warm methanol, and to thisis added a solution of `5 grams sodium in 10 cc. abrv l' solute methanol. The sodium salt lforms ,a

white precipitate, which 'iscoiiected and dried.'

Now 2.25 grams of B-chloroethyl-diethylamine hydrochloride are dissolved, ina few cc. of water,

placed into a separatory funnel and made alka. line With sodium hydroxide solution. The'sepe arated free amine is now taken up With ether and the solution dried with flake .caustic soda. To this solution is added the sodium -methoxy nicotinate and heated on the steam bath under l C O O CHaCHnNKCiHlhfl-NSCI The resulting diethylaminoethyl-G-methoxy nicotinate is soluble in ether, chloroform and alcohols, and insoluble in Water. With inorganic and organic acids it forms addition salts which are more or less soluble in Water. i

Example 2 From 42 grams B-chloroethyldiethylamine hydrochloride the base is prepared as above. To the ether solution 3 grams finely pulverized sodiurn6(iso) propyloxy nicotinatevare added and heated on the steambath under a reux `condenser for 3 hours.` After evaporating the ether an oily residue remains. vThis is taken up with ether and Washed, with Water several times. After evaporating the ether, normal hydrochloric acid is added -to the residueuntil all is dissolvedA and the solution evaporated to dryness. For purication it is `recrystallized from dry acetone. The White crystalline powder melts at 118Ci-A l The formula of this hydrochloride of diethylaminoethyl-G-(iso)propyloxy-nicotinate. is as follows:

l Y. Example 3 From .2.5.- grams- B-chloroethyldiethylamine hydrochloride the base is prepared as above. To the ether solution 2 grams finely pulverized so dium 6-(n)butoxy nicotinate are added and heated on the steam bath under a reux condenser for one and a half hours. After evaporating the ether' an oily residue remains. This residue is treated as in Example 2 and the ob tained hydrochloride of diethylaniinoethyl-6(n) butyloxy nicotinate is` recrystallzed` fllfrom ether-absolute ethanol mixture. It forms ne colorless needles. M. P. 108111,C.; Itis soluble in ether, dioxane and very soluble in alcohols and in water. The base of this substance, and the benzoate, cinnamate, phenylacetate and hexoate form dilcultly crystallizable oils.

From 4.5 grams 'y chloropropyl dibutylamine hydrochloride the base is prepared as previously described. To the ether solution 3.1 grams nely pulverized sodium 6-(n) butoxy nicotinate are added and heated on the steam bath for one and a half hours. After evaporating the ether an oily residue remains. This residue is treated as in Example 3 to obtain the hydrochloride of dibutylaminopropyl6(n) butyloxy nicotinate:

QDCcHlO-LN This substance is soluble in ether, alcohols and water. The base is insoluble in Water. Both the hydrochloride and the free base form a slightly yellowish'colored oil.

,The compounds prepared according to the methods described in the examples possess anesthetic properties. When a small quantity is placed on the tongue, one will promptly observe a lasting anesthetic action. For testing purposes the hydrochloride and other salts of the compounds were prepared and (L5- 2% solutions were used. Rabbits eyes were ooded with the solution for 1 minute. The anesthesia in some cases lasted unusually long. The toxicity tests prove that they are relatively non-toxic.

These new anesthetics can be used in aqueous solutions byv dissolving their salts; the hydrochlorides and benzoates having preference over the other salts. The bases dissolved in oil of sweet almond or other suitable oils can be used for injections or can `be incorporated into ointments.

We do not limit ourselves to the specifically mentioned times, temperatures, quantities, chemicals, or steps of procedure as these are given simply to clearly describe our invention as set forth in our specification 'and' claims, and may be Varied without going beyond the scope of our invention.

' What we claim is:

1. As a medicinal compound having anaesthetic properties, the dialkylamlnoalkanol ester of 6alkoxypyridine-3-carboxylic acid of the following general formula:

in which R' is an alkyl group containing 1 to 6 carbon atoms, R2 is the residue of an alkyl group and R3 is the residue of an alkyl group, these alkyl groups being unsubstituted and selected from /\-o columna I l H Ac R ORN/ in which R is an alkyl group containing 1 to 6 carbon atoms, R2 is the residue of an alkyl group,

R3 is the residue of an alkyl group, these alkyl l 'RO-\N/ in which R is the residue oi an alkyl compound f containing l to 6 carbon atoms, R2 is the `residue of an ethyl group and R3 is the residue of an alkyl group, these alkyl groups being unsubstituted and selected from a group of, monovalent radicals derived from a saturated hydrocarbon.

a. As a medicinal compound having anaesthetic properties, the dialkylaminoalkanolester of 6-alkoXypyridine-3-carboxylic acid of the following general formula:

/\-cooR2N(Ri z i I H Ac R O-\N/ in which R is the residue of an alkyl group" containing l to 6 carbon atoms, R2 is the residue of an ethyl group, R3 is the residue of an alkyl group, these alkyl groups being unsubstituted and selected from a group of monovalent radicals derived from a saturated hydrocarbon and Ac is an acid radical forming a Water soluble salt.v

5. As a medicinal compound` having anaesthetic properties, the dialkylaminoalkanol ester of 6-alkoxypyridine-S-carboxylic acid of the iollowing general formula:

www)

in which R' is the residue of an alkyl group containing l to 6 carbon atoms, R2 is the residue of a propyl group and R3 is the residue of an alkylv group, these alkyl groups being unsubstituted and selected from a group of monovalent radicals derived from a saturated hydrocarbon.

6. As a medicinal compound having anaesthetic properties, the dialkylarninoalkanol ester of 6alkoXypyridine-3-carboxylic acid of the iollowing general formula:

in which R is the residue of an alkyl group containing 1 to 6 carbon atoms, R2 is the residue of a propyl group, R3 is the residue of an alkyl group, these alkyl groups being unsubstituted and seleoted from a group of monovalent radicals derived from a' saturated hydrocarbon and Ac is an acid radical forming a Water soluble salt.

7. As a new medicinal compound having anaesthetic properties, the hydrochloride of diethylarninoethyl-6 iso) propyloxy nicotinate.

8. As a new medicinal compound having anaesthetic properties, the hydrochloride of diethylaminoethyl-S-(n) butyloxy nicotinate.

k9. As a new medicinal compound having anaesthetic properties, the hydrochloride of dibutylaminopropyl-Gm) butyloxy nicotinate.

RAEMER R. RENSHAW. PAUL F. DREISBACH. 

